On Oct. 6, 2004, the Royal Swedish Academy of Sciences declared that the Nobel Prize for Chemistry of that year was awarded to Israel scientists Aaron Ciechanover, Avram Hershko and American scientist Irwin Rose for their discovery of protein degradation process regulated by ubiquitin-proteasome passway (hereinafter referred to as “UPP”). It is indicated that the pathway of protein degradation regulated by ubiquitin-proteasome has a tremendous significance in the area of life.
Ubiquitin (Ub for short) is a highly conserved polypeptide chain consisted of 76 amino acids with a molecular weight of 8.5 kD. A lot of molecular biochemical, cellular, genetic and clinical researches indicated that the process of protein degraded by ubiquitin-proteasome was important for regulation of many physiological processes as well as development of various important human diseases. It is discovered recently that this degradation process also has a great impact on pathogenesis of neurodegenerative diseases, Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Creutzfeld-Jacob disease (CJD) and diabetes.
It has been well-known that proteasome can modulate the level of protein involved in cell cycle control, such as cyclin acting on G1 phase and mitosis phase, cdk inhibitors, tumor suppressor protein and other regulatory proteins. UPP-dependent protein degradation pathway has been confirmed to play an important role in controlling cell reproduction and cell death, and this pathway also has a great influence on nervous system degenerative diseases such as PD, AD and the like. The use of new inhibitors will reveal more newly unknown functions of ubiquitin proteasome.
Up to date, proteasome inhibitors found can be divided into two kinds, peptides and non-peptides. Peptide inhibitors are usually constituted by short peptides and various pharmacophores attached to the C-terminal thereof, wherein the pharmacophores react with the catalytic amino acid residues of proteasome (primarily hydroxy of threonine in the N-terminal) to form a reversible or irreversible covalent complex, while the remainder of the peptide chain selectively combines with other residues in the subunit active site. At the present time, main pharmacophores include aldehyde groups (peptide aldehydes), vinyl sulfone, boronic acid (peptide boronic acids) and α′,β′-epoxy ketone etc.
Compared with peptide aldehyde inhibitors, peptide boronic acid inhibitors have better druggability for the reason that the stability and selectivity of the pharmacophore boronic acid group or boronic ester group of these compounds are better than those of aldehyde group, and that the toxicity of boron substances are very low, and they can finally be degraded into environmentally friendly boronic acid. For example, PS341 (English name is Bortezomib or VELCADE, Chinese name is , also being called as ), , which is a dipeptide boronic acid inhibitor, is a novel anti-tumor drug developed by America Millennium Pharmaceuticals, already been marketed in USA, EU and P.R. China. The drug is mainly administered to the patient suffered from multiple myeloma (MM), who have been received at least two or more treatments, and the drug is the only approved proteasome inhibitor currently used in clinical treatment in the world. The drug can overcome the drug resistance of traditional antitumor drugs, so it brings hope for the treatment of multiple myeloma.
U.S. Pat. No. 5,780,454 discloses a new kind of boronic ester compounds P-AA1-AA1-AA3-B(Z1)(Z2), wherein the compounds include tripeptide boronic ester compounds. However, there are just a few of tripeptide compounds being disclosed, and the structures of said tripeptide compounds are only of two types: L-Leu-L-Leu-L-Leu or L-Leu-L-NaI-L-Leu. The data provided in this patent indicate that the activities of the dipeptide compounds are better than those of the tripeptide compounds.
U.S. Pat. No. 5,693,617 reports tripeptide aldehyde compounds are a type of proteasome inhibitors with high activity. But both the selectivity and stability of these inhibitors are very poor since their pharmacophores are aldehyde groups.
On this basis, the present inventors researched and discovered a new type of tripeptide boronic acid or boronic ester compounds having more desirable proteasome inhibitory activity.